The advantages of transdermal administration of pharmaceutically active agents over other routes is well documented. Among these advantages are: avoidance of gastric irritation, elimination of side effects, evading the problem of hepatic first-pass metabolism, reduction of risks associated with parenteral treatment, delivery of the active agent directly to the bloodstream, and others.
The primary limitation to the widespread use of the transdermal route however is the barrier properties of skin. Many substances do not have the capability of migrating across intact skin. This, of course, is not all that surprising in that one of the skin's primary function is to act as a barrier.
In compact skin, the stratum corneum is quite impermeable, a property conferred primarily from its lipid character. However, both lipoidal and pore pathways do exist in and through the stratum corneum. These pathways are exploited for the transdermal administration of the known transdermally administrable drugs, and as such, the hydrophobic/hydrophilic character of the drug being administered becomes of great importance. The stratum corneum is considered overall to be hydrophobic in nature and substantial resistance is encountered when hydrophilic/ionized molecules attempt to cross it.
One approach to solving the low permeation difficulties is the use of permeation enhancers, materials which increase the flux of the desired agent through the skin. Permeation enhancers can react with either skin components or with the desired agent. In either event the flux of the desired agent is enhanced over that which would be achieved in the absence of the permeation enhancer.
A wide range of enhancers have been proposed, heretofore. Representative disclosures of permeation enhancers in the an include the following: cyclic urea compounds (U.S. Pat. No. 4,677,131), a monovalent alcohol ester (U.S. Pat. No. 4,605,670), dimethyl sulfoxide (U.S. Pat. No. 3,551,554), hydrocarbons, ketones, esters, ethers, alcohols, amines, or sulfones (British Patent 1,504,302), a partial glyceride of a medium chain length fatty acid (U.S. Pat. No. 4,202,888), lower alkyl amides (U.S. Pat. No. 3,472,931), 2-pyrrolidone or N-lower alkyl-2-pyrrolidone (U.S. Pat. No. 4,132,781), C.sub.3 -C.sub.4 diols (U.S. Pat. No. 4,557,943), sugar ester+a sulfoxide or phosphine oxide (U.S. Pat. Nos. 4,130,667, 3,952,099 and 4,046,886), higher alcohols+esters (U.S. Pat. No.4,299,826), ethanol+azone or oleic acid (Eur. Pat. EP 271,983), amines (Jpn Kokai Tokyo Koho JP 62,240,628), oleic acid+2 ethyl- 1,3 hexanediol, ethanol+glycerol monolaurate (U.S. Pat. No. 4,764,379).
Based on these and other references, it is clear that little or no attention has been given to the problem of reducing permeation enhancer induced skin irritation, to the manipulation of active agents per se so as to enhance skin permeation, to drags which permeate the stratum corneum to a significant extent by routes other than the lipoidal pathway, to the implication that particular enhancers often only work with particular active agents.
Several references mentioning isopropanol mixed with other solvents as percutaneous absorption enhancers include THERATECH INC., "Topical pharmaceutical composition with improved skin penetration--containing alkanol and compound, e.g. oleic acid", (EP 267,617, JP 63,211,241), PROCTER AND GAMBLE CO., "Topical composition containing lipophilic pharmaceutical with diol and myristate or laurate ester vehicle for enhanced penetration", (EP 43,738, JP 57,081,408, ZA 8,140,650, CA 1,165,240, DE 3,172,516), Friend et at., "Transdermal delivery of levonorgestral I: alkanols as penetration enhancers in vitro." (J. Control. Rel. 3 (1988) pp. 243-250).
Many pharmaceutically active agents an weak organic acids or bases having the potential to ionize in the physiologic pH range, The extreme hydrophilic character of ionic drugs severely limits their penetration through the lipophilic heterogeneous stratum corneum so that for all practical purposes only the unionized form can pass through the barrier.